Lanthanoid-containing polyoxometalate nanocatalysts in the synthesis of bioactive isatin-based compounds

Lanthanoid-containing polyoxometalates (Ln-POMs) have been developed as effective and robust catalysts due to their Lewis acid–base active sites including the oxygen-enriched surfaces of POM and the unique 4f. electron configuration of Ln. As an extension of our interest in Ln-POMs, a series of as-synthesized nanocatalysts K15[Ln(BW11O39)2] (Ln-B2W22, Ln = La, Ce, Nd, Sm, Gd, and Er) synthesized and fully characterized using different techniques. The Ln3+ ion with a big ionic radius was chosen as the Lewis acid center which is sandwiched by two mono-lacunary Keggin [BW11O39]9− units to form Ln-containing sandwiched type cluster. Consequently, the catalytic activity of nanocatalysts with different Ln was examined in the synthesis of bioactive isatin derivatives and compared under the same optimized reaction conditions in terms of yields of obtained products, indicating the superiority of the nano-Gd-B2W22 in the aforementioned simple one-pot reaction. The effects of different dosages of nanocatalyst, type of solvent, reaction time, and reaction temperature in this catalytic system were investigated and the best results were obtained in the presence of 10 mol% of nano-Gd-B2W22 in water for 12 min at the reflux condition.

Instrumentation. Electrothermal 9200 apparatus was employed to determine the melting point of products. Bruker Tensor 27 FT-IR spectrometer (400-4000 cm -1 region) was used to detect absorbance bands of organic products using a KBr disk containing the compounds. 1 H NMR, 13 C NMR spectra were recorded on a  www.nature.com/scientificreports/ Bruker AQS 400-AVANCE spectrometer at 400 and 100 MHz, respectively, using TMS as an internal standard (DMSO solution). Also, the infrared spectra of catalysts were recorded in the range of 4000-400 cm -1 on a Thermo Nicolet/AVATAR 370 Elemental analysis (CHN) was performed using a Thermo Finnigan Flash EA 1112 microanalyzer. Metal content was measured by the Spectro Arcos ICP-OES spectrometer model 76004555 using in the range of 130-770 nm for ICP spectra. Powder X-ray diffraction (PXRD) data were collected on ASENWARE/AW-XDM300 X-ray powder diffractometer using Cu Kα (λ = 1.54184 Å) radiation at room temperature with the scan range 2θ = 3 to 40° and step size of 0.05° and step time of 1 s. The scanning electron microscope (SEM) analysis, EDS, and EDS mapping were recorded using LEO-1450 VP at an acceleration voltage of 10.00 kV and resolution of about 500 nm (Zeiss, Germany).  (1 M) was stirred for 10 min in air and then the pH was adjusted to 5.0 by dropwise addition of 0.1 M KOH. The resulted mixture was stirred for a further 40 min at 50 °C. Pure crystals of the catalysts were obtained by slow evaporation of the solvent after several days.

Preparation of catalysts.
Synthesis of nanocatalysts. The mixture solution of Ethanol (10 mL), water (15 mL), and Ln-B 2 W 22 crystals (0.03 g) were subjected to ultrasonication (150 W). After 20 min, nanocatalysts were collected by the centrifuge and then washed with cold water (3 × 5 mL) under vacuum. FT-IR spectra (KBr pellet, cm −1 ) of nano-Ln-B 2 W 22 were consistent with their spectra before doing the nano procedure (Fig. S2).
General procedure for the synthesis of spiro-2-amino-4H-pryans. A combination of 1,3-diketone, carbonyl compound (either isatin or acenaphtoquinone), α-cyano compound (either malononitrile or ethyl cyanoactetate), and Gd-B 2 W 22 was stirred in water at ambient temperature until the complete formation of the product was traced by TLC (Fig. 3). Then, the crude product was filtered, washed with water and dissolved in hot ethanol for crystallization. Furthermore, all products were characterized and analyzed by melting points and FT-IR spectra, and the results were compared with those reported in the literature to prove the formation of target products.
General procedure for the synthesis of uracil fused spirooxindoles. A combination of isatin, uracil derivative (either 1,3-dimethyl-6-aminouracil or 6-aminouracil), 1,3-diketone compounds, and Gd-B 2 W 22 was stirred in refluxing water for 8-26 min (Fig. 4). Then, the mixture was filtered, washed well with water and dried at 80 °C. The product was recrystallized for further purification in hot ethanol. All products were characterized by melting point and the characterizations were compared with that of in literature.
Synthesis of pyrroloacridine derivatives. A mixture of isatin, aniline, dimedone and nanocatalyst was refluxed in water for an appropriate time (Fig. 5). By the completion of the reaction, the mixture was cooled down and filtered. Then the crude product was washed well with hot water, and finally crystallized in hot EtOH. The characterization data of products were compared with that published in the literature.  (Ln-B 2 W 22 , Ln = La, Ce, Nd, Sm, Gd, and Er) crystals (microscopic size) of this study were obtained by reaction of the lanthanoid ion with the mono-lacunary Keggin [BW 11 O 39 ] 9− at pH 5 (Figs. 2 and S3). Next, the above crystals were solved and subjected to ultrasonication and then nanocatalysts were collected by the centrifuge (top-down approach). The distribution histograms reveal that the average particle size of catalysts is less than 100 nm upon 20 min of sonication (   www.nature.com/scientificreports/ Also, the SEM showed that the dominant morphology for nanocatalysts is rod-like (Fig. 7). Furthermore, the presence of O, K, Gd, and W in the nanocatalysts is confirmed by the EDS spectrum (Fig. 8). SEM images of La-B 2 W 22 and EDS spectra of other nanocatalysts are given in Supplementary Information (Figs. S9-S14).
It is important to note that infrared spectroscopy is frequently employed technique for the characterization of POMs due to their characteristic metal-oxygen stretching vibrations that occur in the region between 400 and 1000 cm −1 which is known as the fingerprint region for the POMs. As shown in Figs. S1, S2, and Table 1, the overlaid IR spectra strongly suggest the same structural family for all crystalline and nano compounds. Also, the IR spectra of catalysts present a similar vibration pattern with the mono-lacunary Keggin [BW 11 (Fig. 9).
Also, the powder XRD pattern of the catalysts appears at around 9-10° for a 2θ value (similar to other monolacunary Keggin anions) 43 (Supplementary Fig. S15).    Table 2). The Gd-B 2 W 22 nanocatalyst was selected for further tests. Next, the effect of solvent was studied by running the model reaction in polar and non-polar solvents. Finally, the amount of catalyst was optimized to achieve the highest amount of product. The reaction was also repeated with no catalyst furnishing trace amount of product. That's while in the presence of 10 mol% of nanocatalyst, the target product was obtained in 96%. Therefore, ensuring by the effect of a catalyst in this reaction, the generalization was accomplished in water, in the presence of 10 mol% nano-Gd-B 2 W 22 at reflux condition. It is important to note that the Lewis acidity (Z/r 3 ; Z = charge and r = ionic radius) of lanthanoids decreases with an increase in the ionic radii 44 . However, among the Ln-B 2 W 22 (Ln = La, Ce, Nd, Sm, Gd, and Er) catalysts examined, Gd-B 2 W 22 showed better catalytic performance because by reducing the size from Gd to Er, the Er center was sterically hindered by two BW 11 ligands and its Lewis acid site is not well accessible. The one-pot reaction of isatin, α-cyano compound (either malononitrile or ethylcyanoacetate), and 1,3-diketone (either ethyl acetoacetate, dimedone, or barbituric acid) or 3-methyl-1H-pyrazol-5(4H)-one/ 4-hydroxycoumarin or α-naphtol/β-naphtol) gave the favorite products. Notwithstanding, the effect of substituent on isatin ring, the yield of products was found in good to high. By employing acenaphthenequinone instead of isatin, the expected spiro-4H-pyrans were formed in good to high yields. The products obtained from ethylcyanoacetate need a longer reaction time than those obtained from malononitrile that possibly is due to the lower reactivity of ethylcyanoacetate (Table 3). All products were known and identified by comparing their melting points with authentic literature. Some selected NMR spectra are presented in supplementary file (Figs. S16-S47).
In Scheme 1, we propose a sensible mechanism for the preparation of spirooxindole derivatives. First, the Gd-B 2 W 22 catalyst, as a Lewis acid, activates the carbonyl group of the isatin molecule, and then malononitrile, due to alpha-activated hydrogens, will have a nucleophilic attack on activated carbon, which produces intermediate    Table 4.

Compound ν as (B-O a ) ν s (B-O a ) ν(W-O a ) ν as (W-O t ) ν as (W-O b ) and ν as (W-O c )
Next, the catalytic effect of nano-Gd-B 2 W 22 was studied in the production of pyrroloacridine compounds through the one-pot reaction of isatin, aromatic amines, and dimedone. The generalization of this reaction was considered using different aromatic amine-bearing electron-donating and electron-withdrawing substituents. The expected pyrroloacridine derivatives were formed in wonderful yield within short reaction times as summarized in Table 5 (Fig. 10).   22 was evaluated on the model reaction and it was recycled up to 6 runs by simple filtration with a gradual decrease in activity from 96 to 85% in the corresponding product (Fig. 10). In addition, to elucidate whether the recycling process can result in any change in the catalyst's morphology and structure, the SEM image as well as FTIR spectra of the recycled nano-Gd-B 2 W 22 catalyst were recorded (Fig. 11). These results support that the structure of the nano-Gd-B 2 W 22 underwent several reactions was preserved, but some agglomeration is evident.

Concluding remarks
In the present study, a series of isostructural lanthanoid-containing polyoxometalate nanocatalysts Ln-B 2 W 22 (Ln = La, Ce, Nd, Sm, Gd, and Er) were synthesized and characterized using a suite of analytical techniques. Among these nanocatalysts, the gadolinium-containing POM (Gd-B 2 W 22 ) showed remarkable catalytic performance for the synthesis of bioactive isatin derivatives including spiro-2-amino-4H-pryans, uracil fused spirooxindoles, and pyrroloacridine derivatives under the reflux condition in high yields and short reaction times (8-26 min). Also, further studies are underway in our laboratory to extend the application of these family nanocatalysts to other coupling reactions.

Scheme 1.
The reasonable mechanism for the synthesis of spirooxindole derivatives.

Data availability
The raw/processed data that supports the findings of this study is available from the corresponding authors upon reasonable request.